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The treatment of visceral leishmaniasis (kala-azar) often requires prolonged therapy. In this open-label, randomized study involving more than 400 patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. In patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. Some 90% of patients with visceral leishmaniasis (kala-azar) in India and nearly 50% of patients worldwide live in the northeastern Indian state of Bihar. 1 In Bihar, treatment with liposomal amphotericin B is effective in regimens as brief as 5 days, 1 – 3 offering a remedy for the principal drawback of all other antileishmanial agents: a prolonged duration of treatment. 1 , 4 However, when such a regimen of liposomal amphotericin B was abbreviated still further, to a single infusion of 5 or 7.5 mg per kilogram of body weight, the efficacy of the drug (90 to 91% 4 – 6 ) did not reach the . . .

Globally, cryptococcal meningitis is a leading cause of mortality among people with AIDS, despite the availability of effective amphotericin B–based therapy. In this trial in sub-Saharan Africa, the efficacy of two simpler treatment regimens was assessed.

Background Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. Trial registration ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Determining the best therapy for HIV-associated cryptococcal meningitis in resource-poor settings is controversial. In this trial in Vietnam, initial therapy with amphotericin B with flucytosine had better outcomes than amphotericin B alone or with fluconazole. There are approximately 1 million cases of cryptococcal meningitis annually and 625,000 deaths. 1 Treatment guidelines recommend induction therapy with amphotericin B deoxycholate (0.7 to 1 mg per kilogram of body weight per day) and flucytosine (100 mg per kilogram per day). 2 However, this treatment has not been shown to reduce mortality, as compared with amphotericin B monotherapy. 2 , 3 Flucytosine is frequently unavailable where the disease burden is greatest, and concerns about cost and side effects have limited its use in resource-poor settings. 4 Fluconazole is readily available, is associated with low rates of adverse events, and has good penetration into cerebrospinal . . .

Talaromyces marneffei is a dimorphic fungus that causes substantial disease in Asia, especially among persons infected with the human immunodeficiency virus. In this randomized, controlled trial, initial therapy with amphotericin B was found to be superior to itraconazole. The dimorphic fungus Talaromyces (previously Penicillium ) marneffei causes a life-threatening mycosis in immunocompromised persons living in or traveling to Southeast Asia, China, and India. 1 Talaromycosis (previously penicilliosis) is a major cause of human immunodeficiency virus (HIV)–related death; its prevalence is surpassed only by the prevalence of tuberculosis and cryptococcosis, 2 and it leads to 4 to 15% of HIV-related hospital admissions in regions in which the disease is endemic. 3 – 7 Talaromycosis is increasingly diagnosed among patients who are not infected with HIV but who have other immunodeficiency conditions 8 and is reported to be the second most common cause of all . . .

In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. CTRI/2017/04/008421.

Fungal keratitis (FK), a major cause of blindness, remains challenging to treat due to poor drug penetration and antifungal resistance. Amphotericin-B (AmB), a water-insoluble and low-permeability, necessitates innovative delivery systems to improve its therapeutic efficacy. AmB was encapsulated within oleosomes (Ole) prepared using the ethanol injection method, using phosphatidylcholine (Lipoid S100) and sodium oleate, resulting in nanosized spherical globules. The optimized Ole were characterized, then the selected Ole were incorporated into sodium polyacrylate/PEG/chitosan-based microneedles (AmB-Ole/MNs) to improve ocular delivery by creating transient microchannels on the eye surface. The optimized Ole showed a droplet size of (175 ± 0.78 nm), polydispersity index of (0.33 ± 0.04), zeta potential of (31 ± 0.43 mV), high entrapment efficiency (91±0.63%), and improved stability, bioavailability, and controlled drug release. The AmB-Ole/MNs system increases corneal penetration and contact time via transient microchannels in the eye surface, achieving sustained drug delivery over 72 hours with 70% ex vivo permeation over 80 hours compared to AmB. In vitro antifungal activity and histopathological examination showed that the AmB-Ole/MNs system has potent biofilm disruption (>90%) and 27 mm and 32 mm zones of inhibition against and Aspergillus niger, respectively. The Cytotoxicity test showed reduced AmB toxicity with biocompatibility and in vivo , ocular tolerance by targeting TLR4/NLRP3 pathways and histopathological studies. The AmB-Ole/MNs system as an innovative ocular delivery platform for fungal keratitis offers sustained drug release, enhanced permeation, potent antifungal activity, and reduced toxicity. AmB-Ole/MNs showed promise for ocular AmB delivery for FK.

Chitosan nanoparticles have gained attention as drug delivery systems (DDS) in the medical field as they are both biodegradable and biocompatible with reported antimicrobial and anti-leishmanial activities. We investigated the application of chitosan nanoparticles as a DDS for the treatment of cutaneous leishmaniasis (CL) by preparing two types of chitosan nanoparticles: positively charged with tripolyphosphate sodium (TPP) and negatively charged with dextran sulphate. Amphotericin B (AmB) was incorporated into these nanoparticles. Both types of AmB-loaded nanoparticles demonstrated in vitro activity against Leishmania major intracellular amastigotes, with similar activity to unencapsulated AmB, but with a significant lower toxicity to KB-cells and red blood cells. In murine models of CL caused by L. major, intravenous administration of AmB-loaded chitosan-TPP nanoparticles (Size = 69 ± 8 nm, Zeta potential = 25.5 ± 1 mV, 5 mg/kg/for 10 days on alternate days) showed a significantly higher efficacy than AmBisome® (10 mg/kg/for 10 days on alternate days) in terms of reduction of lesion size and parasite load (measured by both bioluminescence and qPCR). Poor drug permeation into and through mouse skin, using Franz diffusion cells, showed that AmB-loaded chitosan nanoparticles are not appropriate candidates for topical treatment of CL.

This multinational, double-blind trial compared caspofungin, an echinocandin, with liposomal amphotericin B as empirical antifungal therapy in 1095 patients with persistent fever and neutropenia. Caspofungin was as efficacious as the standard therapy and was better tolerated, with less nephrotoxicity and fewer drug-related adverse events. This multinational trial compared caspofungin with liposomal amphotericin B. The results support an effective new option for empirical antifungal therapy in high-risk patients. Invasive fungal infections are important causes of illness and death in patients with neutropenia who receive chemotherapy for cancer or who undergo hematopoietic stem-cell transplantation. 1 – 3 Persistent fever in patients with neutropenia who are receiving broad-spectrum antibiotics may be the only clinical indication of an invasive fungal infection. Amphotericin B and its lipid formulations, as well as triazoles (fluconazole, itraconazole, and voriconazole), have been studied as empirical antifungal agents in patients with persistent fever and neutropenia. 4 – 11 However, these agents may be associated with toxicity and adverse drug interactions and have a limited spectrum of activity, erratic bioavailability, unpredictable pharmacokinetics, . . .

Summary Liposomal amphotericin B (AmBisome®) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be non-inferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical therapy in patients with febrile neutropenia and in those with disseminated histoplasmosis, and is an option for the treatment of AIDS-associated cryptococcal meningitis, and for invasive Candida spp. or Aspergillus spp. infections. Pharmacological Properties Amphotericin B, a macrocyclic, polyene antifungal agent, is thought to act by binding to ergosterol, the principal sterol in fungal cell membranes and Leishmania cells. This results in a change in membrane permeability, causing metabolic disturbance, leakage of small molecules and, as a consequence, cell death. In vitro and in vivo studies have shown that liposomal amphotericin B remains closely associated with the liposomes in the circulation, thereby reducing the potential for nephrotoxicity and infusion-related toxicity associated with conventional amphotericin B. Amphotericin B shows very good in vitro activity against a broad spectrum of clinically relevant fungal isolates, including most strains of Candida spp. and Aspergillus spp., and other filamentous fungi such as Zygomycetes. Liposomal amphotericin B has proven effective in various animal models of fungal infections, including those for candidiasis, aspergillosis, fusariosis and zygomycosis. Liposomal amphotericin B also shows immuno-modulatory effects, although the mechanisms involved are not fully understood, and differ from those of amphotericin B deoxycholate and amphotericin B colloidal dispersion. In adult patients with febrile neutropenia, intravenous liposomal amphotericin B has nonlinear pharmacokinetics, with higher than dose-proportional increases in exposure being consistent with reticuloendothelial saturation and redistribution of amphotericin B in the plasma compartment. Liposomal amphotericin B is rapidly and extensively distributed after single and multiple doses, with steady-state concentrations of amphotericin B attained within 4 days and no clinically relevant accumulation of the drug following multiple doses of 1–7.5 mg/kg/day. In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue. Elimination of liposomal amphotericin B, like that of amphotericin B deoxycholate, is poorly understood; its route of metabolism is not known and its excretion has not been studied. The terminal elimination half-life is about 7 hours. No dosage adjustment is required based on age or renal impairment. Clinical Efficacy In several randomized, double-blind trials (n = 73–1095) in adult and/or paediatric patients, liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections, including invasive candidiasis, candidaemia, invasive mould infection (mainly aspergillosis), histoplasmosis and cryptococcal meningitis. All agents were administered as an intravenous infusion; the typical dosage for liposomal amphotericin B was 3 mg/kg/day. Treatment was generally given for 1–2 weeks. Participants in trials evaluating empirical therapy had neutropenia and a persistent fever despite antibacterial treatment and had received chemotherapy or undergone haematopoietic stem cell transplantation. As empirical therapy in adult and paediatric patients, liposomal amphotericin B appeared to be as effective as amphotericin B deoxycholate (approximately 50% of patients in each group achieved treatment success) or amphotericin B lipid complex (approximately 40% of liposomal amphotericin B recipients experienced treatment success). Of note, in the first trial, results of the statistical test to determine equivalence between treatments were not reported. In the second trial, efficacy was assessed as an ‘other’ endpoint. In another trial, caspofungin was shown to be noninferior to liposomal amphotericin B, with approximately one-third of patients in each group experiencing treatment success. Liposomal amphotericin B was significantly more effective than amphotericin B deoxycholate for the treatment of moderate to severe disseminated histoplasmosis in patients with AIDS, with 88% and 64% of patients, respectively, having a successful response. Liposomal amphotericin B was noninferior to amphotericin B deoxycholate for the treatment of cryptococcal meningitis in terms of mycological success. Micafungin therapy was shown to be noninferior to liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidiasis. In a substudy in paediatric patients, which was not powered to determine noninferiority, liposomal amphotericin B was as effective as micafungin for the treatment of candidaemia or invasive candidiasis. In this patient population, within each trial, 90% of adult patients and approximately three-quarters of paediatric patients in both treatment groups experienced a successful response. In patients with invasive mould infection (mainly aspergillosis), there was no difference in efficacy between a higher dosage of liposomal amphotericin B (10mg/kg/day) and the standard dosage (3 mg/kg/day), with 46% and 50% of patients experiencing a favourable overall response. Tolerability In well designed clinical trials, liposomal amphotericin B was generally at least as well tolerated as other lipid-associated formulations of amphotericin B and better tolerated than amphotericin B deoxycholate in adult and paediatric patients. Compared with other amphotericin B formulations, liposomal amphotericin B treatment was associated with a lower incidence of infusion-related adverse events and nephrotoxicity. A higher than recommended dosage of liposomal amphotericin B (10 mg/kg/day) was associated with an increased incidence of nephrotoxicity compared with the standard dosage (3 mg/kg/day), although the incidence of infusion-related reactions did not differ between treatment groups. In general, liposomal amphotericin B treatment was not as well tolerated as echinocandin therapy in well designed clinical trials. As empirical therapy or for the treatment of confirmed invasive fungal infections in adult patients, liposomal amphotericin B recipients experienced more infusion-related events and nephrotoxicity than caspofungin or micafungin recipients. There was no difference in the incidence of these adverse events between the liposomal amphotericin B and micafungin groups in a study in paediatric patients.